There are a number of serious diseases affecting the central nervous system. These diseases, referred to as neuropathologies, include Down's syndrome and Alzheimer's disease. Down's syndrome is a congenital condition involving moderate to severe mental deficiency. Alzheimer's Disease is a form of dementia marked by progressive intellectual deterioration without focal, motor or sensory signs. It is an insidious, progressive, debilating disease of unknown etiology afflicting almost two million Americans, most of them elderly.
Although the etiology of Alzheimer's disease is unknown, researchers have identified three histopathological structures which are present in the brains of Alzheimer's patients: neurofibrillary tangles, neuritic (senile) plaques, and cerebrovasculature plaques. Neurofibrillary tangles are intracellular accumulations of fibrous material in the cell bodies of affected neurons, mainly in the hippocampus, amygdala and neocortex. Neuritic and cerebrovascular plaques are found in highest concentration in the hippocampus and neocortex and result from a pathological deposition of amyloid precursor protein(s) (APP) or fragments thereof in these regions, such as described in U.S. Pat. No. 4,666,829, incorporated herein by reference. It should be noted that the term amyloid, as used in a neuropathological context, refers to the deposition of APP and its fragments into plaques. This differs from the usage of the term in the general, histopathological context. Specifically, when applied to neuropathological plaques, the term most commonly refers to the A4 amino acid fragment of APP. In standard histopathological uses the term amyloid refers to a refractive, insoluble, noncellular material.
It appears that protease inhibitor systems may participate in certain neuropathologies. In both Down's syndrome and Alzheimer's disease, an insoluble peptide termed .beta.-amyloid aggregates into neuritic plaques (Allsop et al., (1983) Brain Res. 259, 348-352; Glenner et al., (1984) Biochem. Biophys. Res. Commun. 122, 1131-1135 Masters et al., (1985) Proc. Nat'l. Acad. Sci. U.S.A. 82, 4245-4249; Castan et al., (1986) Biochem. Biophys. Res. Commun. 141, 782-789; Kirschner et al., (1987) Proc. Nat'l. Acad. Sci. U.S.A. 84, 6953-6957). .beta.-Amyloid is derived from one or more .beta.-amyloid precursor proteins (.beta.-APP) (Kang et al., (1987) Nature 325, 733-736; Kitaguchi et al., (1988) Nature 331, 530-532; Ponte et al., (1988) Nature 331, 525-527; Tanzi et al., (1988) Nature 331, 528-530), which are normal neuronal constituents (Card et al., (1988) Neuron 1, 835-846). The generation of .beta.-amyloid appears to result from inappropriate processing of .beta.-APP by one or more proteases (Glenner et al., (1987) in Banbury Report 27: Molecular Neuropathology of Aging (Davies, P., and Finch, C. E., eds) pp. 253-255, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.; Kang et al., (1987) Nature 325, 733-736; Grundke-Iqbal et al., (1989) Proc. Nat'l. Acad. Sci. U.S.A. 86, 2853-2857; Weidemann et al., (1989) Cell 57, 115-126). Specifically, the amino terminus of .beta.-amyloid is formed through hydrolysis of .beta.APP on the carboxyl side of methionine.sup.596 (Kang et al., (1987) Nature 325, 733-736). Based upon the affinities of known proteases for primary protein structure, such a cleavage event is predicted to result through the action of a chymotrypsin-like enzyme (Barrett et al., (1980) Mammalian Proteases, Vol. 1, Academic Press, New York; Lorand (1981) Methods Enzymol 80, 1-919).
.beta.-Amyloid is one of two identified integral components of neuritic plaques. The second known component is .alpha.-1-antichymotrypsin (.alpha.-1-AChy) (Abraham et al., (1988) Cell 52, 487-501), a protease inhibitor that forms sodium dodecyl sulfate-resistant bonds with chymotrypsin-like enzymes (Travis et al., (1978) Biochemistry 17, 5651-5656). It is not yet known whether .alpha.-1-AChy might be associated with neuritic plaques by virtue of its binding to a chymotrypsin-like protease which itself is an integral plaque component. .alpha.-1-AChy has also been reported in normal brain (Justice et al., (1987) J. Cell. Biochem 34, 227-238; Abraham et al., (1990) Neurobiol Aging, in press).